J Bacteriol Virol.  2019 Mar;49(1):12-26. 10.4167/jbv.2019.49.1.12.

Effector Pathways of Toll-like Receptor-inducible Innate Immune Responses in Macrophages

• Jo EK
• Suh HW
• Park JK

• KMID: 2442584
• DOI: http://doi.org/10.4167/jbv.2019.49.1.12

Abstract

Toll-like receptors (TLR) are well-characterized pattern recognition receptors that can recognize and respond to diverse pathogen-associated or danger-associated molecular patterns during infection. TLR signaling in macrophages triggers in the intracellular signaling pathways through the recruitment of various adaptor and signaling proteins, and results in the activation of effector mechanisms and pathways that are important for host defense to intracellular bacteria. Effector mechanisms include inflammatory responses, cytokine generation, production of reactive oxygen species, and antimicrobial proteins. Accumulating studies showed that autophagy is a key pathway in the maintenance of homeostasis and housekeeping functions during infection and inflammation. In this review, we summarize the major effector pathways and mechanisms in the activation of TLR-inducible innate immune responses in macrophages. In addition, we focus the emerging evidence of crosstalk between autophagy and TLR-mediated signaling in terms of effector function of innate immune responses. A better understanding of effector functions by the activation of TLR-mediated signaling cascades contributes to the development of new therapeutics and vaccines against various intracellular pathogenic infections.

Keyword

TLR; Cytokine; Antimicrobial Protein; Effectors; Autophagy; Innate Immunity

MeSH Terms

Autophagy
Bacteria
Homeostasis
Housekeeping
Immunity, Innate*
Inflammation
Macrophages*
Reactive Oxygen Species
Receptors, Pattern Recognition
Toll-Like Receptors
Vaccines
Reactive Oxygen Species
Receptors, Pattern Recognition
Toll-Like Receptors
Vaccines

Figure

• 

  Figure 1 An overview of TLR-induced intracellular signaling pathways in innate immune cells. Upon TLR signaling, the intracellular signaling cascades involve the actions of numerous adaptors MyD88, TRIF, MAL/TIRARAP, or TRAM, and multiple signaling molecules. In particular, MyD88 is recruited by all TLR molecules, whereas TRIF is utilized by TLR3 and 4. The recruitment of MyD88 activates IRAK kinase family members, which associates with E3 ubiquitin ligase TRAF6 to activate TAK1 protein kinase complex. This leads to the activation of both NF-κB and mitogen-activated protein kinase (MAPK) pathways (ERK1/2, p38, and JNK) for proinflammatory cytokine generation. The other adaptor TRIF interacts with both TRAF6 and TRAF3, to facilitate the activation of TAK1 complex and TBK1 pathways, leading to the activation of type I interferon responses. In the sophisticated process, uncoordinated 93 homolog B1 (UNC93B 1) and leucine-rich repeat containing protein (LRRC) 59, are required for the endosomal TLR trafficking from ER to endosomal structures.

• 

  Figure 2 Multiple functions of antimicrobial proteins in innate immune responses. TLR-induced intracellular signaling pathways culminate into the activation of innate effector pathways including the generation of antimicrobial proteins. Two important antimicrobial peptides, cathelicidins and defensins, function in various aspects of biological responses, i.e., the regulation of inflammation, phagocytosis, autophagy, as well as antimicrobial effects, in innate immune cells.

• 

  Figure 3 A schematic overview of macroautophagy and xenophagy in mycobacterial infection. Macroautophagy process include three steps: initiation (formation of phagophore), elongation into double-membraned autophagosomal structure, and its maturation by lysosomal fusion. Xenophagy process is well-characterized in mycobacterial infection. During Mtb infection, xenophagy is activated by cytoplasmic release of Mtb, which can be ubiquitinated by E3 ligases Parkin and Smurf1. Then ubiquitinated Mtb phagosomes are recognized by autophagic receptors p62 and NDP52, which contain domains for interaction with ubiquitinated cargos and LC3-containing autophagic machinery. It is also well-known that, several innate immune signals including TLR, vitamin D receptor signaling, IFN-γh distinct mechanisms involving IRGM (for IFN-γ), cathelicidins (for vitamin D receptor signaling), and TBK1 (for TLR) in monocytes/macrophages.

• 

  Figure 4 Figure 4. TLR-mediated regulation of antibacterial autophagy. TLR signaling activation in innate immune cells results in the activation of antibacterial autophagy. TLR7 signaling activates autophagy through MyD88; TLR4 stimulation induces autophagy through a TRIF-dependent pathway. TLR2/1 stimulation activates AMPK-dependent functional vitamin D signaling activation, leading to the induction of autophagy activation and antimicrobial responses. Either TLR2 or TLR4 stimulation activates autophagy through a serine protease inhibitor PAI-2 via stabilization of Beclin 1. In addition, TLR3, 7, 9, and UNC93B1, are required for the activation of antibacterial autophagy. TLR8 stimulation activates the expression of genes involved in vitamin D signaling and cathelicidin-dependent autophagy in human macrophages.

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